Allogeneic stem cell transplantation for children and adolescents/young adults with <i>de novo</i> blastic phase chronic myeloid leukemia in the tyrosine kinase inhibitor era
Authors: Hisashi Ishida, Hiroyuki Shimada, Akihiko Tanizawa, Yutaka Shimazu, Takayoshi Tachibana, Noriko Doki, Takahide Ara, Yayoi Matsuo, Miho Nara, Tomomi Toubai, Kazuko Ino, Hirohisa Nakamae, Keisuke Kato, Koji Kato, Atsushi Sato, Moeko Hino, Kimikazu Matsumoto, Yoshiko Atsuta, Masahiro Yasui, Tokiko Nagamura‐Inoue
Journal: American Journal of Hematology (2023)

The analysis of 165 children and adolescents/young adults with de novo blastic phase chronic myeloid leukemia showed disease status at hematopoietic stem cell transplantation was a strong prognostic factor and clearly separated the patient outcomes. To the Editor: Chronic myeloid leukemia (CML) incidence increases with age, thus the disease is rare during childhood, comprising 2%–3% of childhood leukemia.1 At diagnosis, the vast majority of children with CML present in chronic phase (CP); thus, children or adolescents/young adults (AYAs) diagnosed with blastic phase CML (de novo CML-BP) are extremely rare.2 While tyrosine kinase inhibitors (TKIs) have significantly improved the survival of patients with CML, hematopoietic stem cell transplantation (HSCT) still plays an important role for some high-risk patients. However, few studies have investigated prognostic factors related to HSCT outcomes for children with CML in the TKI era,3, 4 and those focusing on de novo CML-BP are even more limited. Here, we investigated the characteristics and outcomes of 165 patients diagnosed with de novo CML-BP under 40 years old who received TKI treatment and their first HSCT between 2000 and 2019 in Japan. Details for methods are provided in Supplementary Methods S1. Characteristics of patients included in this study are presented in Table S1. The median follow-up period of survivors was 5.0 years after HSCT (range, 0.2–15.9 years). Comparison of the characteristics of children (0–17 years old) and AYA patients (18–39 years old) demonstrated that the former received donor–recipient sex mismatched HSCT more frequently and were more likely to undergo HSCT with better disease status. Median time from diagnosis to HSCT did not differ significantly between the two age. Among the 165 patients, 17 received reduced-intensity conditioning (RIC) before HSCT, and information on reasons for choosing a RIC regimen was available for 9 patients. The most frequent reason was patient complications present at the time of HSCT (n = 6), and the second most common reason was to avoid future long-term complications (n = 3). Five-year event-free survival (EFS) of all included patients was 64.1% (95% confidence interval [CI], 55.9%–71.2%), and 5-year overall survival (OS) was 70.3% (95% CI, 62.0%–77.1%). Cumulative incidence of relapse at 5 years was 21.2% (95% CI, 15.2%–27.9%), and cumulative incidence of non-relapse mortality at 5 years was 14.7% (95% CI, 9.5%–20.9%). These outcomes did not differ significantly between children and AYA patients as the 5-year EFS of children was 72.6% (95% CI, 55.1%–84.2%), and that of AYA patients was 61.7% (95% CI, 52.2%–69.9%; p = .226; Figure 1A), and the 5-year OS did not differ between them (p = .507; Figure 1B). Causes of death were also similar between age groups (Table S2). Univariate analysis showed that year of HSCT, performance status at HSCT, conditioning regimen, human leukocyte antigen disparities, and disease status at HSCT were significant prognostic factors for EFS (Table S3). Disease status at HSCT was a strong prognostic factor as 5-year EFS was 84.1% (95% CI, 72.9%–90.9%) for patients receiving HSCT in complete or major molecular response (CMR/MMR), 61.1% (95% CI, 43.3%–74.8%) for those undergoing HSCT in complete or partial cytogenetic response (CCyR/PCyR), and 37.5% (95% CI, 21.8%–53.2%) for those who could not achieve major cytogenetic response (MCyR) at HSCT (p < .001; Figure 1C). Disease status at HSCT was also identified as a prognostic factor for OS (p < .001; Figure 1D). There was no difference in EFS between those receiving myeloablative conditioning (MAC) regimens with or without total-body irradiations (data not shown). Multivariate analysis of EFS revealed that disease status at HSCT (CCyR/PCyR vs. CMR/MMR, hazard ratio [HR] 2.46, p = .038; and no MCyR vs. CMR/MMR, HR 3.18, p = .014) and conditioning regimen (RIC vs. MAC, HR 3.89, p = .001) were significant adverse prognostic factors (Figure 1E). The differences in outcome according to disease status or conditioning regimen were maintained when we focused separately on each age group (Figures S1 and S2). As evaluation of disease status at the molecular level has recently become more common, we conducted similar analysis including only patients receiving HSCT in recent years (2010–2019), and disease status at HSCT remained as a prognostic factor in univariate and multivariate analysis, although no-MCyR versus CMR/MMR lost significance (HR 3.80, p = .052) due to small sample size (Tables S4 and S5, and Figure S3). By using a national data set with no age restrictions, we successfully compared the characteristics and outcomes between children and AYA patients with de novo CML-BP who received HSCT. The 5-year EFS and OS rates of all included patients were 64.1% and 70.3%, respectively, which were better than those of previous reports of adult patients (OS < 40%).5, 6 In the current study, we identified several differences in characteristics between children and AYA with CML-BP, while no significant differences in outcomes were identified between these two groups. In the current cohort, children were more likely to receive HSCT in a better disease status, and received donor–recipient sex mismatched HSCT more frequently than AYA patients. The former could be because more intensive chemotherapy was administered before HSCT for younger patients in this cohort, but information on the details of pre-HSCT therapies was lacking. In the current cohort, patients receiving HSCT at CMR or MMR showed excellent outcomes, with 5-year EFS of 84.1%. On multivariate analysis adjusted for known prognostic factors, better disease status (CCyR/PCyR vs. CMR/MMR or no MCyR vs. CMR/MMR) was identified as a significant favorable prognostic factor (Figure 1E). Disease status was previously suggested to predict outcome in adult patients with CML-BP5; however, to our best knowledge, this is the first study to demonstrate similar findings in children and AYA. Furthermore, our study demonstrates that an assessment of disease status at the molecular level enables us to clearly separate the outcomes of these patients. It should be noted that this does not necessarily imply a causal relationship between the disease status and patient outcome. As delayed HSCT can lead to disease recurrence among patients with CML-BP,6 it would be preferable to offer timely HSCT rather than to delay HSCT while pursuing a deeper molecular response. Nevertheless, our data are valuable to set treatment goals for children and AYA patients with de novo CML-BP before receiving HSCT. MAC regimen was also identified as an independent favorable prognostic factor on multivariate analysis adjusted for age group and known prognostic factors (Figure 1E). Moreover, MAC regimen remained a significant prognostic factor when we analyzed only children or AYA patients separately. In the previous literatures, conflicting results have been reported regarding the feasibility of administering RIC regimens in adults with CML-BP, and this remains a matter of debate.1, 5 Our findings should be carefully evaluated since it was impossible to eliminate selection bias, given the retrospective design of our study. In our cohort, although we could not identify any significant difference in background characteristics between those receiving MAC and RIC (Table S6), the most frequent reason for choosing a RIC regimen was patient complications present at the time of HSCT; accordingly, there may be selection bias between patients receiving RIC and MAC. Although RIC was identified as an adverse prognostic factor in multivariate analysis, it remains possible that RIC is a suitable option for selected patients with de novo CML-BP. A prospective study eliminating selection bias is warranted to clarify the feasibility of RIC regimen administration for these patients, although this will be challenging due to the limited number of patients. In general, children and AYA with CML are reported to have more aggressive disease than adults1, 2; however, in the current analysis, age group was not associated with outcome for AYA versus children on multivariate analysis (HR, 1.17; 95% CI, 0.50–2.73). Further, disease status and conditioning regimen were identified as significant prognostic factors for EFS on multivariate analysis, and these two factors remained significant when we analyzed children or AYA patients separately, suggesting that these two factors are more strongly associated with the patient outcome than the age group. This study has several limitations. First, detailed information on treatment before HSCT was lacking. As we identified disease status at HSCT as a strong prognostic factor, optimization of pre-HSCT treatment will be critical for patients with de novo CML-BP. Second, information on lymphoid or myeloid crisis was also absent. A larger predominance of lymphoid immunophenotype has been reported for children with CML-BP relative to adults,2 which could affect the selection of pre-HSCT treatment and subsequent outcome.6 Third, information on post-HSCT TKI administration was largely unavailable and could not be analyzed in this study, and the influence of post-HSCT TKIs on patient outcomes remains the subject of considerable discussion. In the current cohort, of 46 patients with information available, 39 (84.8%) received post-HSCT maintenance with a TKI. Further study is warranted to clarify this point. In conclusion, better disease status at HSCT and myeloablative conditioning regimen were identified as significant favorable prognostic factors in children and AYA with CML-BP, but the latter can be explained by selection bias. Age group was not associated with EFS in univariate or multivariate analyses. These results will help to optimize HSCT settings for children and AYA patients with de novo CML-BP. Hisashi Ishida: Conceptualization; methodology; formal analysis; writing—original draft. Hiroyuki Shimada: Methodology; formal analysis; writing—review and editing. Akihiko Tanizawa: Methodology; formal analysis; writing—review and editing. Yutaka Shimazu: Methodology; formal analysis; writing—review and editing. Takayoshi Tachibana: methodology; formal analysis; writing—review and editing. Noriko Doki: Data collection and writing—review and editing. Takahide Ara: Data collection; writing—review and editing. Yayoi Matsuo: Data collection; writing—review and editing. Miho Nara: Data collection; writing—review and editing. Tomomi Toubai: Data collection; writing—review and editing. Kazuko Ino: Data collection; writing—review and editing. Hirohisa Nakamae: Data collection; writing—review and editing. Keisuke Kato: Data collection; writing—review and editing. Koji Kato: Data collection; data curation; writing—review and editing. Atsushi Sato: Data collection; data curation; writing—review and editing. Moeko Hino: Data collection; data curation; writing—review and editing. Kimikazu Matsumoto: Data collection; data curation; writing—review and editing. Yoshiko Atsuta: Data curation; formal analysis; writing—review and editing. Masahiro Yasui: Methodology; formal analysis; writing—review and editing. Tokiko Nagamura-Inoue: Methodology; formal analysis; writing—review and editing. Hirohisa Nakamae has received honoraria and research funding from Bristol-Myers Squibb, Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., and Pfizer Inc. outside the submitted work. All the other authors declare no conflicts of interest. Not applicable. DATA S1. Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.